Tyrosyl-tRNA synthetase (TyrRS) and Gene Regulation
Overview and Function of TyrRS in Gene Regulation: Tyrosyl-tRNA synthetase (TyrRS) is an enzyme that traditionally plays a role in protein assembly--specifically the aminoacylation of proteins. TyrRS recognize the codes present in gene transcripts and link them to the corresponding amino acids. Specifically, TyrRS recognize genetic codes that specify the amino acid tyrosine. However, under instances of oxidative stress, this enzyme can activate genes responsible for protecting DNA from damage, thus having a genetic regulatory effect. Oxidative stress is defined as an imbalance between reactive oxygen species (ROS) and the body's ability to detoxify them. ROS are a normal byproduct of oxygen metabolism that can drastically increase in number during times of environmental stress, like when the body is exposed to UV-light or radiation. Over time, oxidative stress can cause significant damage to the cells, and is responsible for a number of health concerns (cancer, growths) as well as playing a significant role in accelerating the aging process. Mechanism Through Which Gene Expression is Regulated: * Oxidative stress, which typically decreases protein synthesis, triggers TyrRS to translocate from the cytosol to the nucleus * The nuclear-localized TyrRS activates transcription factor E2F1 to upregulate the expression of DNA damage repair genes such as BRCA1 and RAD51. The activation is achieved through direct interaction of TyrRS with genes necessary for transcriptional control To simplify, a damaging event (like prolonged exposure to UV-light) can disrupt a cell, causing it to die. As the cell dies, TyrRS (which is already present in the cell) will migrate out in 2 pieces, each of which carries an immune-stimulating signal to other cells. The TyrRS will then travel into the nucleus of nearby cells, causing surges of activity in genes linked to DNA protection and repair To test just how effective TyrRS was at protecting the cell from DNA damage, scientists at the Scripps Institute over-expressed the enzyme (in zebra fish) and found that TyrRS strongly protects against UV-induced DNA double-strand breaks, whereas restricting TyrRS nuclear entry completely abolishes the protection. As stated by lead study author Xiaohua Wu, "We found that TyrRS promotes the most conservative and error-free homologous recombination pathway for DNA repair, which would help maintain the stability of the cell genome whenever it sustains damage.” The Broader Picture: What TyrRS Can Mean for Our Health & Science: The fact that TyrRS, an enzyme that is already present within our cells and plays a utilitarian role in normal protein synthesis, can have a protective effect on our DNA during times of environmental stress carries important implications. For one, TyrRS has the potential to be used therapeutically, where flooding the nucleus with the enzyme could provide DNA protection to individuals who have experienced radiation or toxin exposure. Secondly, there may be a way to extrapolate TyrRS' use as a DNA protector to repair hereditary DNA defects that cause disease. And finally, the fact that oxidative stress causes the TyrRS enzymes to be released into nuclei in the first place points to a potential use of the enzyme in the billion-dollar anti-ageing industry. Purposeful over-expression of the enzyme could be used to combat free-radicals and other species known to cause cellular damage. As is apparent, there are many potential uses for the discovery of TyrRS' protective effect on our genomes, and it is quite miraculous to think that such a basic, evolutionarily-ancient enzyme can have such a prolific influence when envrionmental conditions are sub-optimal. References: Fuccelli, F. et al. Preventative Activity of Olive Oil Phenolic Compounds on Alkene Epoxides Induced Oxidative DNA Damage on Human Peripheral Blood Mononuclear Cells. Nutrition and Cancer, 2014. PubMed.gov Kunsch, Charles. Circulation Research, 1999; 85: 753-766. The American Heart Association Journals Meyer, Gene. Genetic Regulatory Methods, 9. University of South Caroline School of Medicine Ono, Mika. News and View, Issue 28, October 2014. The Scripps Institute Wei, N. et al. DNA Oxidative Stress Diverts tRNA Synthetase to Nucleus for Protection against DNA Damage. Departments of Chemical Physiology and Cell and Molecular Biology, The Scripps Research Institute. PubMed.gov